Targeted bacteriophage T4 nanoparticles reverse HIV-1 latency in human T cell line models

A major barrier for HIV-1 eradication is the latent virus reservoir containing stably integrated and silent proviruses in CD4⁺ T cells. Targeted reactivation and removal of this latent reservoir is a potential strategy for HIV-1 cure, but remains a major challenge. Here, we investigated whether CD4-targeted bacteriophage T4 capsid nanoparticles that mimic the HIV envelope can reactivate HIV-1 latency. The nanoparticles were arrayed with CD4-binding CD4-DARPin, or the HIV-1 gp140 envelope trimer. When exposed to J-Lat T cell model of HIV-1 latency or primary T-lymphocytes from human PBMCs, these nanoparticles activated CD4⁺ T cells without causing global T cell activation, which led to the activation of HIV-1 proviral transcription, viral protein production, and release. Intriguingly, the observed T cell activation and HIV-1 latency reversal do not involve the classic PKC or NFAT pathways and did not lead to cytokine storm. These studies indicate that engineered non-infectious bacteriophages can be exploited for HIV-1 cure and targeted T cell therapies.